FDA数据完整性和cGMP合规指南最新

FDA检查员指导手册CP 7356.002：药品生产检查程序目录对现场报告的要求 (35)第一部分背景 (36)第二部分执行 (36)2.1.目的 (36)2.2.策略 (36)2.2.1.对生产企业两年一度的检查（包括重新包装商、合同实验室等） (36)2.2.2.系统性检查 (37)2.2.3.对原料药及制剂生产的系统性检查计划 (38)2.2.3.1.质量系统 (38)2.2.3.2.厂房设施与设备系统 (38)2.2.3.3.物料系统 (38)2.2.3.4.生产系统 (38)2.2.3.5.包装和贴签系统 (38)2.2.3.6.实验室控制系统 (39)2.3.程序管理指导 (39)2.3.1.定义 (39)2.3.1.1.监督性检查 (39)2.3.1.2.达标检查 (40)2.3.1.3.受控状态 (40)2.3.1.4.药品工艺 (40)2.3.1.5.药品生产检查 (41)第三部分检查 (41)3.1.检查活动 (41)3.1.1.总则 (41)3.1.2.检查方法 (42)3.1.2.1.全面性检查的选择 (43)3.1.2.2.简略性检查的选择 (43)3.1.2.3.综合性检查范围 (43)3.1.3.系统性检查范围 (43)3.1.3.1.质量系统 (44)3.1.3.2. 厂房设施与设备系统 (44)3.1.3.3.物料系统 (45)3.1.3.4.生产系统 (46)3.1.3.5.包装和贴签系统 (47)3.1.3.6.实验室控制系统 (48)3.1.4.取样 (49)3.1.5.检查组组成 (49)3.1.6.报告 (49)第四部分分析 (50)第五部分法律性/行政性策略 (50)5.1.质量系统 (51)5.2.厂房设施和设备 (51)5.3.物料系统 (51)5.4.生产系统 (52)5.5.包装和贴签系统 (52)5.6.实验室控制系统 (52)对现场报告的要求作为法律行动的一部分，所有针对因在执行cGMP方面有缺陷而采取的检查，均要向药品评价和研究中心的达标办公室呈交一份现场检查报告(EIR)。

数据完整性的法规依据1. 2010 版GMP 对于文件和记录的数据完整性的要求第一百五十九条应建立文件的起草、修订、审核、批准、替换或撤销、复制、保管和销毁等管理制度，并有相应的文件分发、撤销、复制、销毁的记录。

第一百六十三条原版文件复制时，不得产生任何差错;复制的文件应清晰可辨。

第一百六十五条记录应留有数据填写的足够空格。

记录应及时填写，内容真实，字迹清晰、易读，不易擦掉。

第一百六十六条应尽可能采用生产和检验设备自动打印的记录、图谱和曲线图等，并标明产品或样品的名称、批号和记录设备的信息，操作人应签注姓名和日期。

第一百六十七条记录应保持清洁，不得撕毁和任意涂改。

记录填写的任何更改都应签注姓名和日期，并使原有信息仍清晰可辨，必要时，应说明更改的理由。

记录如需重新誊写，则原有记录不得销毁，而应作为重新誊写记录的附件保存。

第一百六十八条与本规范有关的每项活动均应有记录，所有记录至少应保存至药品有效期后一年，确认和验证、稳定性考察的记录和报告等重要文件应长期保存，以保证产品生产、质量控制和质量保证等活动可以追溯。

每批药品应有批记录，包括批生产记录、批包装记录、批检验记录和药品放行审核记录等与本批产品有关的记录和文件。

批记录应由质量管理部门负责管理。

第一百六十九条如使用电子数据处理系统、照相技术或其它可靠方式记录数据资料，应有所用系统的详细规程;记录的准确性应经过核对。

如果使用电子数据处理系统，只有受权人员方可通过计算机输入或更改数据，更改和删除情况应有记录;应使用密码或其它方式来限制数据系统的登录;关键数据输入后，应由他人独立进行复核。

用电子方法保存的批记录，应采用磁带、缩微胶卷、纸质副本或其它方法进行备份，以确保记录的安全，且数据资料在保存期内应便于查阅。

可见，在GMP规定中无论是系统自动生成的电子记录还是手写的纸质记录都属于GMP要求的记录，并且都从属于GMP 文件管理规定的范畴。

GMP 对于记录要求的核心内容是"记录你所做的"，即真实记录发生过的事情，并且记录应该及时，重要记录需要由他人复核确认;需要更改记录时应按要求进行(理由、签名、日期)更改并保留原信息清晰可辨;记录应按照要求的频率进行，并保存至要求的期限。

FDA对数据完整性检查发现的主要缺陷近年来，FDA在进行cGMP检查时发现涉及数据完整性的违规越来越多，数据完整性是保证药品安全性、有效性的重要组成部分，同时也是FDA保障公众健康的重要组成部分。

在联邦法规中涉及数据完整性的条款主要有：①要求数据被完好保存以防丢失。

（21CFR 212.110(b)）②要求确保备份数据完整准确，防止数据被篡改、不慎删除或丢失。

（21CFR211.68（b））③要求某些活动在执行时应即时记录，并且实验室控制应该是科学合理的。

（21CFR211.100和21CFR211.160）④要求保留原始记录、真实副本或者原始记录的准确复制。

（21CFR211.180）⑤要求记录所有执行的检验、所有检验的完整信息及数据。

（21CFR211.188、21CFR211.194和21CFR 212.60（g））FDA对数据完整性检查发现以下缺陷类型：一、审计追踪功能关闭1.什么是审计追踪？审计追踪是一种安全的、由计算机生成的、有时间标识的电子记录，可重建电子记录的生成、修改或删除的整个过程。

记录关于谁、什么、何时、为什么的时序表。

2.主要相关缺陷①在红外光谱仪中的原始数据被篡改或删除；②未进行访问控制；③未在红外光谱仪中进行动态的审计追踪；④篡改文件名称。

3.警告信举例2015年12月FDA基于对浙江HZ制药公司原料药现场检查发出警告信，其中违规行为包括FDA审查其HPLC电子记录，发现该企业审计追踪功能并没有激活，而工厂的检验员却在当日进样80次来进行含量测定和杂质检验，FDA将此违规行为列入警告信中。

二、未审查审计追踪警告信举例2016年1月29日，FDA向Ipca Laboratories发出警告信，其中违规行为包括该企业质量部门未审查其原始电子记录，以至于质量部门不能发现文件被改写、删除或覆盖，FDA将此违规行为列入警告信中。

三、未设置管理员权限1.如何限制计算机系统的访问权限？采用适当的控制措施，保证只有经过授权的人才能修改计算机化的生产和检验记录（MPCRs）、录入实验的记录数据以及其他记录。

FDA：关于数据完整性指南十八问和实验室审计缺陷案例分析2018年年底，FDA关于《数据完整性及CGMP合规指南》完成了定稿发布。

本指南澄清了数据完整性在21CFR210,211和212中所要求的现行药品生产质量管理规范中的作用，它提供了关于按照CGMP要求创建和处理数据的机构看法。

一般情况下，FDA指南文件不具有规定依法强制执行责任,它充许企业使用灵活和基于风险的策略预防和检测数据完整性问题。

本指南是实验室数据完整性的一个重要参考文献。

无论是官方认证、检查，还是客户审计，用它来指导实验室的准备工作可以更深入、更全面。

作为实验室人员，对于这份指南的理解也决定了技术人员掌握数据完整性和CGMP合规的程度。

本文摘录了这份指南的18个问题，具体的回答在原指南中可以查阅。

同时我们根据这份定稿的指南分析了FDA近两年检查的8个案例中关于实验室部分的缺陷，以飨读者，限于笔者水平有限，意见仅供参考。

FDA关于行业指南：数据完整性与药品CGMP合规的18个问题：1请澄清以下术语在用于CGMP记录时的含义。

2.什么时候允许宣布一个CGMP结果无效并在判定批合格时排除该结果？3.是否需要对计算机系统中的每个CGMP工作流均进行验证？4.应如何限制对CGMP计算机系统的访问？5.为什么FDA会关切使用共用计算机系统登录账号？6.空白表格要如何受控？7.审计追踪应由谁审核？8.审计追踪应多久审核一次？9.电子副本是否可用作电子或纸质记录的准确复制本？10.是否可以将单机版计算机化实验室仪器，如FT/R仪器中的原始电子记录保存为纸质打印件或静态记录？11.主生产和检验记录中是否可使用电子签名替代手动签名？12.电子数据何时成为一份CGMP记录？13.为什么FDA在警告信中将“系统适用性”或检测、准备或系统平衡运行中使用实际样品作为缺陷？14.是否可以只保存重新处理后的实验室色谱图得到的最终结果？15.是否可以在书面CGMP质量体系以外以非正式方式处理内部提醒或关于质量问题的信息,如潜在数据造假问题？16.是否要将防止和发现数据完整性问题培训作为常规CGMP培训计划的一部分？17.是否应允许FDA查看电子记录？18.FDA建议如何解决数据完整性问题？案例1公司：BayerPharmaAG地点：德国检查官：JustinA.BoydQC缺陷一：没有保存和复核所有的检测记录。

Guidance for IndustryQuality Systems Approach to Pharmaceutical CGMP Regulations业界指南——制药企业CGMP规范的质量体系U.S. Department of Health and Human ServicesFood and Drug AdministrationCenter for Drug Evaluation and Research (CDER)Center for Biologics Evaluation and Research (CBER)Center for Veterinary Medicine (CVM)Office of Regulatory Affairs (ORA)September 2006Pharmaceutical CGMPs目录Ⅰ简介Ⅱ背景和目的A 背景B 指南的目标C 指南适用范围D 指南的组织结构Ⅲ CGMP和现代质量系统的概念A 质量B 质量设计和产品开发C 质量风险管理D CAPA（纠偏和预防措施）E 变更控制F 质量部门G 六系统检查模式IV 质量系统模型A 管理责任1 授予领导权2 构建组织3 建立符合要求的质量系统4 建立方针政策、目标和计划5 系统审核B资源1 授予领导权2人员提高3厂房和设备4对外包工作的控制C生产制造1产品和生产工艺的设计、开发和文件化2检查输入3运作的执行和监控4 非一致性D 评估活动1 数据的趋势分析2 内部审核3 质量风险管理4 纠偏措施5 预防措施6 推动改善V 结论术语表（本指南代表了FDA对质量体系当前的思考。

它既没有为任何人也不是为赋予任何人利益而制定。

并且其操作也不对FDA或公众形成约束。

只要能够满足对现行法规和规范的要求你可以采用其它方法。

如果你有兴趣讨论其它方法，可以联系负责执行本指南的FDA人员。

如果你无法确认恰当的FDA人员，可以拨打本指南公布的电话。

FDA警告信：涉及数据完整性（印度Megafine）近日，FDA对印度Megafine公司发布了警告信，警告内容主要涉及数据造假和偏差调查不彻底等缺陷。

其中关于稳定性数据（12个月）造假（替换图谱）的缺陷，尽管回复24个月和36个月的稳定性时间点的检测结果仍符合质量标准，官方仍不接受这种做法。

因为并没有说明在所存在的数据造假的程度，没有调查确定其它药品批次的检测数据准确性，也没有提交所实施的纠正措施来确保销售的药品的质量。

另外一个问题可能跟造假类似，即未经授权进入或改变数据，以提供足够的控制来防止数据篡改和遗漏。

这是数据完整性的问题，也是数据管理不充分导致的。

安装高版本的网络版色谱数据软件可以防止这类问题。

还有一个问题也是数据完整性的，在这种大环境下企业如果不重视数据完整性，抱着侥幸心里基本上都是要随时狗带的了。

原文如下：The U.S. Food and Drug Administration (FDA) inspected your drug manufacturing facility, Megafine Pharma Limited at No. 201, Village Lakhmapur, Dindori, Nashik, from May 11-15, 2015.FDA于2015年5月11-15日对你工厂进行了检查。

This warning letter summarizes significant deviations from current good manufacturing practice (CGMP) for active pharmaceutical ingredients (API).此警告信中列出了原料药重大CGMP缺陷。

Because your methods, facilities, or controls for manufacturing, processing, packing, or holding do not conform to CGMP, your API are adulterated within the meaning of Section 501(a)(2)(B) of the Federal Food, Drug, and Cosmetic Act (FD&C Act), 21 U.S.C. 351(a)(2)(B).由于你们生产、加工、包装或保存的方法、设施或控制不符合CGMP要求，你们的原料药被认为是掺假。

·医药论坛·药品色谱检测中的数据完整性问题探讨沈丽欢（上海华测品创医学检测有限公司 上海 201112）摘要 当前药品色谱检测中的数据完整性问题主要包括计算机化系统的访问管理、非合规测试（如单针进样、中止序列）、数据的再处理和手动积分、元数据和审计追踪、超标结果管理等，这些问题可能会影响公司产品质量的可信度，严重的可能导致上市药品的频繁召回。

本文回顾国家药品监督管理局食品药品审核查验中心发布的2017年度、2021年度药品检查工作报告和美国食品药品管理局（FDA）官网近2年公布的警告信中关于药品色谱检测中的数据完整性问题，并讨论了规避上述问题的措施。

关键词 数据完整性计算机化系统色谱检测中图分类号：R951 文献标志码：C 文章编号：1006-1533(2024)03-0059-05引用本文沈丽欢. 药品色谱检测中的数据完整性问题探讨[J]. 上海医药, 2024, 45(3): 59-63.Discussion of data integrity issues in chromatography laboratorySHEN Lihuan[Centre Testing International Pinchuang (Shanghai) Co., Ltd., Shanghai 201112, China] ABSTRACT Currently, data integrity issues in drug chromatography laboratory were mainly classified as access management of computerized systems, testing into non-compliance (such as single needle injection, aborted runs), data reprocessing and manual integration, metadata and audit trail, and managing out of specification results, and so on. The reputationof company’s product quality may suffer significantly, and may cause frequent marketed drugs recalls in serious cases. This article reviews the 2017 and 2021 annual drug inspection work report issued by Center for Food and Drug Inspection of NMPA, and the warning letter published on the official website of the United States Food and Drug Administration (FDA) in the past 2 years pertaining to majority of data integrity issues in drug chromatography laboratory, and discusses measures to avoid these troubles.KEY WORDS data integrity; computerized system; chromatography laboratory在德国工业4.0和我国《中国制造2025》背景下，智能化生产设施、检测设备和与之配套的计算机化系统被逐步应用到制药行业中[1]。

美国食品和药品管理局Cosmetic Good Manufacturing Practice Guidelines化妆品良好生产规范指南联邦食品、药品和化妆品法案（The Federal Food, Drug and Cosmetic Act, 以下简称FD&C 法案）禁止在州际直接贸易的化妆品是掺杂的或贴假标签的情况。

(Sec. 301)以下4种情况下，化妆品被认为是可能掺杂的：1．在用户使用过程中，由于化妆品本身含有或在包装容器中有潜在的、对人体有害的成分而使用户受到伤害的；2．本身含有不洁成分的；3．本身含有禁用成分，例如：未认可的色素添加剂；4．在不卫生条件下生产的、或保留的，可导致产品伤害用户有害或被不洁成分所污染。

以下几种情况下，化妆品被认为可能会认为贴假标签(Sec. 602)：1.虚假的标签或存在误导信息的标签2.显著违反了联邦食品、药品和化妆品法案的要求在标签上声明的信息要求3.在容器上有误导的信息为了确定化妆品生产厂家是否保留或发货了掺杂的、或是贴假标签的化妆品，和防止这些违反了FD&C 法案生产的化妆品流入市场，法律给了FDA进入这些化妆品工厂检查的权利，包括检查相关工厂的设备，成品，原料，容器和标签。

（见Sec. 704(a) of the FD&C Act.）如果工厂严格的根据良好的操作规范（GMP）的要求生产，将最低限度的减少掺杂的，或贴假标签的情况。

随后的化妆品指导，引用于FDA检查操作手册（FDA's Inspection Operations Manual），可以作为指南，用来有效的进行自我检查除。

良好的检查得分则意味着工厂执行了良好的操作规范（GMP）的要求。

指南1．建筑物和设施：检查是否a.用于生产或存放化妆品的建筑物应大小合适，设计和结构应保证设备进出不受阻碍，材料存放整洁，操作卫生以及正确的清洁和维护；b.地面，墙壁和天花板结构表面应光滑，易于清洁，并保持干净和良好状况；c.安装的固定装置，管道的滴水或者冷凝水不会污染化妆品原料，器具，以及与化妆品原料，散装产品或成品接触的设备的表面；d.照明和排风系统应满足预期员工操作和舒适的要求；e.供水，清洗和卫生设施，地面排水和废水系统应充分满足清洁操作的要求，和设备、器具的清洁要求，以及满足员工的需要并易于让员工保持个人清洁2．设备：检查是否a.加工、盛放、中转和灌装过程使用的设备和器具应设计合理，使用的材料和工艺能防止腐蚀、污垢的堆积、以及被润滑油、灰尘或者消毒剂污染；b.器具，运送管道以及和化妆品接触的设备表面应维护良好，并定期清洁和消毒；c.清洁和消毒后的便携式设备和器具应妥善放置，与化妆品接触的设备表面应罩住，以防止飞溅，灰尘或其他污染物3．员工: 检查是否a.监督化妆品的生产或者控制的员工应具有一定的教育背景，培训和/或经验来执行指定的监督工作；b.为防止化妆品掺杂，与化妆品原料，散装成品或化妆品接触表面直接接触的员工，应穿戴适合的工作服，手套，头套等，并保持良好的个人清洁；c.吃东西，喝水，或者抽烟都应严格限制在制定的区域。

数据完整性和CGMP合规行业指南指南草案美国卫生与人类服务部食品药品管理局药物评价和研究中心（CDER ）生物制品评价和研究中心（CBER ）兽药中心（CVM2016年4月发布药品质量/生产标准（CGMP）目录I. 介绍II. 背景III. 问答1. 因涉及CGMP记录，请明确以下术语：a. 什么是“数据完整性”b. 什么是“元数据”c. 什么是“审计追踪”d. 当涉及到记录形式时，FDA如何使用术语“静态”和“动态”？e. FDA如何使用§ 211.68(b)中的术语“备份”？f. § 211.68中，在“计算机或相关系统”中的“系统”是什么？2. 何时允许将CGMP数据从决策制定中排除？3. 我们计算机系统上的每个工作流均需要被验证？4. 如何限制对CGMP计算机系统的访问？5. 为什么FDA关注计算机系统共用登录账户的使用？6. 应如何控制空白文件 ？7. 审计追踪应多长时间审查一次？8. 应由谁来审查审计追踪？9. 电子副本可否用作纸质或电子记录的准确复制品？10.对于单机计算机实验仪器，例如FT-IR（傅立叶变换红外光谱）仪，保存纸质打印件或静态记录而不是原始电子记录是否可接受？11. 对于主生产和控制记录，可否使用电子签名替代手书签名？12. 电子数据何时成为CGMP记录？13. 为什么FDA在警告信中援引“系统适用性”或试检、预检、或平衡运行中使用实际样品？14. 仅保留从重新处理的实验室色谱中得到的最终结果是否可接受？15. 与质量问题（例如潜在的数据伪造）有关的内部建议，能否在记录的CGMP质量体系之外非正式的处理？16.应将对人员培训发现数据完整性问题作为日常CGMP培训计划的一部分吗？17. 允许FDA检查员查看我的电子记录吗？18. FDA建议如何解决在检查中、警告信中或其它监管行动中发现的数据完整性问题？数据完整性和CGMP合规行业指南1本指南体现了食品药品管理局（FDA）关于这一主题的最新见解。

怎样解读FDA的数据完整性数据完整性是一个非常广泛的话题。

它可以包括：没有维护好支持cGMP的原始数据记录，没有维护好支持市场销售的资质，同时也包括数据安全性问题（例如共用密码），或者更严重的数据造假或国际攻击销毁等。

虽然，数据完整性问题为实验室最主要、最常见的问题，但是不意味着只有在实验室才有这样的问题，在研发部门、生产部门、市场部门，甚至是药事管理部门都广泛存在数据完整性问题。

最近，FDA针对数据完整性的活动非常多。

在FDA官方网站，你可以找到数以百计的针对数据完整性的例子。

这些现象说明：数据完整性是FDA检查所重点关注的，相关企业需要引起足够的重视。

Part 1：企业如何准备和应对数据完整性的检查？如何应对数据完整性的检查，对于很多公司可能都不是一个很新鲜的领域。

但是，数据完整性问题将会对企业的业务和发展造成巨大的风险。

如：数据完整性的问题可能会造成新药、仿制药等的上市申请延迟；造成已经上市产品的销售限制。

虽然需要花费更多的财力，对于一些公司，适当的使用第三方服务以提供审计、审查或预演，可能是一种应对检查的捷径。

但从长远看，企业自身仍需要逐步巩固和建立自检自查的能力。

那么，企业如何准备和应对数据完整性的检查？我们将之简单归纳为为三步走：第一步，确定数据确实符合正常的日常操作。

例如：数据是记录在纸上还是以电子的形势记录？是否有第二个人检查验证这些记录？这些记录的检查验证应该由负责人，经理或者质量部门的人员进行检查。

第二步，内部的审计应该包括数据完整性的检查。

对于内部审计的项目，需要包括一个对涉及的所有部门的非常严格完善的数据完整性评估；并且，建议使用公司其他地区部门的人员或者请第三方进行审计检查，以确保审计结果的独立性和不受影响性。

比如说，供应商的资质验证也是数据完整性里面一个重要的环节。

第三步，建立内部奖励机制。

对于勇于讲出不符合规范要求的员工应该给予奖励，包括对于数据完整性的质疑。

Part 2：FDA 警告信中，常见的数据完整性问题数据完整性问题是1980年的仿制药企业丑闻的主要核心问题，当时的一些仿制药的公司被发现在对FDA提交的申请中提供了假数据。

数据完整性和CGMP合规行业指南指南草案美国卫生与人类服务部食品药品管理局药物评价和研究中心（CDER ）生物制品评价和研究中心（CBER ）兽药中心（CVM2016年4月药品质量/生产标准（CGMP）目录I. 介绍II. 背景III. 问答1. 因涉及CGMP记录，请明确以下术语：a. 什么是“数据完整性”b. 什么是“元数据”c. 什么是“审计追踪”d. 当涉及到记录形式时，FDA如何使用术语“静态”和“动态”？e. FDA如何使用§ 211.68(b)中的术语“备份”？f. § 211.68中，在“计算机或相关系统”中的“系统”是什么？2. 何时允许将CGMP数据从决策制定中排除？3. 我们计算机系统上的每个工作流均需要被验证？4. 如何限制对CGMP计算机系统的访问？5. 为什么FDA关注计算机系统共用登录账户的使用？6. 应如何控制空白文件 ？7. 审计追踪应多长时间审查一次？8. 应由谁来审查审计追踪？9. 电子副本可否用作纸质或电子记录的准确复制品？10.对于单机计算机实验仪器，例如FT-IR（傅立叶变换红外光谱）仪，保存纸质打印件或静态记录而不是原始电子记录是否可接受？11. 对于主生产和控制记录，可否使用电子签名替代手书签名？12. 电子数据何时成为CGMP记录？13. 为什么FDA在警告信中援引“系统适用性”或试检、预检、或平衡运行中使用实际样品？14. 仅保留从重新处理的实验室色谱中得到的最终结果是否可接受？15. 与质量问题（例如潜在的数据伪造）有关的内部建议，能否在记录的CGMP质量体系之外非正式的处理？16.应将对人员培训发现数据完整性问题作为日常CGMP培训计划的一部分吗？17. 允许FDA检查员查看我的电子记录吗？18. FDA建议如何解决在检查中、警告信中或其它监管行动中发现的数据完整性问题？数据完整性和CGMP合规行业指南1本指南体现了食品药品管理局（FDA）关于这一主题的最新见解。

Compliance WithCGMPGuidance for IndustryDRAFT GUIDANCEThis guidance document is being distributed for comment purposes only.Comments and suggestions regarding this draft document should be submitted within 60 days of publication in the Federal Register of the notice announcing the availability of the draft guidance. Submit electronic comments to . Submit written comments to the Division of Dockets Management (HFA-305), Food and Drug Administration, 5630 Fishers Lane, rm. 1061, Rockville, MD 20852. All comments should be identified with the docket number listed in the notice of availability that publishes in the Federal Register.For questions regarding this draft document, contact (CDER) Karen Takahashi 301-796-3191; (CBER) Office of Communication, Outreach and Development, 800-835-4709 or 240-402-8010; or (CVM) Jonathan Bray 240-402-5623.U.S. Department of Health and Human ServicesFood and Drug AdministrationCenter for Drug Evaluation and Research (CDER)Center for Biologics Evaluation and Research (CBER)Center for Veterinary Medicine (CVM)April 2016Pharmaceutical Quality/Manufacturing Standards (CGMP)Compliance WithCGMPGuidance for IndustryAdditional copies are available from:Office of Communications, Division of Drug InformationCenter for Drug Evaluation and ResearchFood and Drug Administrationth10001 New Hampshire Ave., Hillandale Bldg., 4 FloorSilver Spring, MD 20993-0002Phone: 855-543-3784 or 301-796-3400; Fax: 301-431-6353Email: druginfo@/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htmand/orOffice of Communication, Outreach and DevelopmentCenter for Biologics Evaluation and ResearchFood and Drug Administration10903 New Hampshire Ave., Bldg. 71, Room 3128Silver Spring, MD 20993-0002Phone: 800-835-4709 or 240-402-8010Email: ocod@/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/default.htmand/orPolicy and Regulations Staff, HFV-6Center for Veterinary MedicineFood and Drug Administration7519 Standish Place, Rockville, MD 20855U.S. Department of Health and Human ServicesFood and Drug AdministrationCenter for Drug Evaluation and Research (CDER)Center for Biologics Evaluation and Research (CBER)Center for Veterinary Medicine (CVM)April 2016Pharmaceutical Quality/Manufacturing Standards (CGMP)TABLE OF CONTENTSI.INTRODUCTION............................................................................................................. 1 BACKGROUND ............................................................................................................... 1 QUESTIONS AND ANSWERS....................................................................................... 2 Please clarify the following terms as they relate to CGMP records:.. (2)II.III.1. a. What is “data integrity”? (2)b. What is “metadata”? (3)c. What is an “audit trail”? (3)d. How does FDA use the terms “static” and “dynamic” as they relate to record formats? (3)e. How does FDA use the term “backup” in § 211.68(b)? (4)f. What are the “systems” in “computer or related systems” in § 211.68? (4)2.3.4.5.6.7.8.9. When is it permissible to exclude CGMP data from decision making?.................................... 4 Does each workflow on our computer system need to be validated? ........................................ 4 How should access to CGMP computer systems be restricted? ................................................ 5 Why is FDA concerned with the use of shared login accounts for computer systems?........... 6 How should blank forms be controlled? ...................................................................................... 6 How often should audit trails be reviewed?................................................................................. 6 Who should review audit trails?................................................................................................... 6 Can electronic copies be used as accurate reproductions of paper or electronic records?.. (7)10. Is it acceptable to retain paper printouts or static records instead of original electronicrecords from stand-alone computerized laboratory instruments, such as an FT-IR instrument? .711. Can electronic signatures be used instead of handwritten signatures for master productionand control records? (8)12. When does electronic data become a CGMP record? (8)13. Why has the FDA cited use of actual samples during “system suitability” or test, prep, orequilibration runs in warning letters? (9)14. Is it acceptable to only save the final results from reprocessed laboratorychromatography? (9)15. Can an internal tip regarding a quality issue, such as potential data falsification, be handledinformally outside of the documented CGMP quality system? (9)16. Should personnel be trained in detecting data integrity issues as part of a routine CGMPtraining program? (10)17. Is the FDA investigator allowed to look at my electronic records? (10)18. How does FDA recommend data integrity problems identified during inspections, inwarning letters, or in other regulatory actions be addressed? (10)1Data Integrity and Compliance With CGMP Guidance for Industry 1 2345 This draft guidance, when finalized, will represent the current thinking of the Food and Drug Administration (FDA or Agency) on this topic. It does not establish any rights for any person and is not binding on FDA or the public. You can use an alternative approach if it satisfies the requirements of the applicable statutes and regulations. To discuss an alternative approach, contact the FDA staff responsible for this guidance as listed on the title page.6 7 89 10 11121314 1516 17 18 19 I. INTRODUCTIONThe purpose of this guidance is to clarify the role of data integrity in current good manufacturing practice (CGMP) for drugs, as required in 21 CFR parts 210, 211, and 212. Part 210 covers Current Good Manufacturing Practice in Manufacturing, Processing, Packing, or Holding ofDrugs; General; part 211 covers Current Good Manufacturing Practice for Finished20 Pharmaceuticals; and part 212 covers Current Good Manufacturing Practice for Positron21 22 2324 25 26 27 28 2930 31 32 33 Emission Tomography Drugs. This guidance provides the Agency’s current thinking on thecreation and handling of data in accordance with CGMP requirements.FDA expects that data be reliable and accurat e (see the “Background” section). CGMPregulations and guidance allow for flexible and risk-based strategies to prevent and detect data integrity issues. Firms should implement meaningful and effective strategies to manage their data integrity risks based upon their process understanding and knowledge management oftechnologies and business models.In general, FDA’s guidance documents do not establish legally enforceable responsibilities.Instead, guidances describe the Agency’s current thinking on a topic and should be viewed only as recommendations, unless specific regulatory or statutory requirements are cited. The use of the word should in Agency guidances means that something is suggested or recommended, but 34 not required.3536 3738 39 40 II. BACKGROUNDIn recent years, FDA has increasingly observed CGMP violations involving data integrity during CGMP inspections. This is troubling because ensuring data integrity is an important component of industry’s responsibility to ensure the safety, efficacy, and quality of drugs, and of FDA’s41 ability to protect the public health. These data integrity-related CGMP violations have led to1This guidance has been prepared by the Office of Pharmaceutical Quality and the Office of Compliance in the Center for Drug Evaluation and Research in cooperation with the Center for Biologics Evaluation and Research, theCenter for Veterinary Medicine, and the Office of Regulatory Affairs at the Food and Drug Administration.4243 numerous regulatory actions, including warning letters, import alerts, and consent decrees. The underlying premise in §§ 210.1 and 212.2 is that CGMP sets forth minimum requirements to44 assure that drugs meet the standards of the Federal Food, Drug, and Cosmetic Act (FD&C Act)45 regarding safety, identity, strength, quality, and purity.2 Requirements with respect to data46 integrity in parts 211 and 212 include, among other things:474849505152535455565758 § 211.68 (requiring that “backup data are exact and complete,” and “secure from alteration, inadvertent erasures, or loss”);§ 212.110(b) (requiring that data be “stored to prevent deterioration or loss”);§§ 211.100 and 211.160 (requiring that certain activities be “documented at the time of performance” and that laboratory controls be “scientifically sound”);§ 211.180 (requiring that records be retained as “original records,” “true copies,” or other “accurate reproductions of the original records”); and§§ 211.188, 211.194, and 212.60(g) (requiring “complete information,” “complete data derived from all tests,” “complete record of all data,” and “complete records of all tests performed”).59 Electronic signature and record-keeping requirements are laid out in 21 CFR part 11 and apply to60616263646566676869707172737475 certain records subject to records requirements set forth in Agency regulations, including p arts210, 211, and 212. For more information, see guidance for industry Part 11, Electronic Records; Electronic Signatures — Scope and Application.3 The guidance outlines FDA’s current thinkingregarding the narrow scope and application of part 11 pending FDA’s reexamination of part 11as it applies to all FDA-regulated products.III. QUESTIONS AND ANSWERS1. Please clarify the following terms as they relate to CGMP records:a. What is “data integrity”?For the purposes of this guidance, data integrity refers to the completeness,consistency, and accuracy of data. Complete, consistent, and accurate data shouldbe attributable, legible, contemporaneously recorded, original or a true copy, andaccurate (ALCOA).42FDA’s authority for CGMP comes from FD&C Act section 501(a)(2)(B), which s tates that a drug shall be deemed adulterated if “the methods used in, or the facilities or controls used for, its manufacture, processing, packing, or holding do not conform to or are not operated or administered in conformity with current good manufacturing practice to assure that such drug meets the requirement of the act as to safety and has the identity and strength, and meets the quality and purity characteristics, which it purports or is represented to possess.”3CDER updates guidances periodically. To make sure you have the most recent version of a guidance, check the FDA Drugs guidance Web page at/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm.4For attributable, see §§ 211.101(d), 211.122, 211.186, 211.188(b)(11), and 212.50(c)(10); for legible see §§211.180(e) and 212.110(b); for contemporaneously recorded (at the time of performance) see §§ 211.100(b) and 211.160(a); for original or a true copy see §§ 211.180 and 211.194(a); and for accurate see §§ 211.22(a), 211.68, 211.188, and 212.60(g).Contains Nonbinding RecommendationsDraft — Not for Implementation7677b. What is “metadata”?7879808182838485 Metadata is the contextual information required to understand data. A data value is by itself meaningless without additional information about the data. Metadata is often described as data about data. Metadata is structured information that describes, explains, or otherwise makes it easier to retrieve, use, or manage data. For example, the number “23” is meaningless without metadata, such as an indication of the unit “mg.” Among other things, metadata for a particular pieceof data could include a date/time stamp for when the data were acquired, a user ID of the person who conducted the test or analysis that generated the data, the instrument ID used to acquire the data, audit trails, etc.868788899091 Data should be maintained throughout the record’s retention period with all associated metadata required to reconstruct the CGMP ac tivity (e.g., §§ 211.188 and 211.194). The relationships between data and their metadata should be preserved in a secure and traceable manner.9293 c. What is an “audit trail”?9495969798 For purposes of this guidance, audit trail means a secure, computer-generated, time-stamped electronic record that allows for reconstruction of the course of events relating to the creation, modification, or deletion of an electronic record. An audit trail is a chronology of the “who, what, when, and why” of a record. For example, the audit trail for a high performance liquid chromatography (HPLC) run could include the user name, date/time of the run, the integration parameters used, and details of a reprocessing, if any, including change justification for the reprocessing.99 100 101 102 103104 105 106 107 108 109 110 111 112 113 114 115 116 117 118 119 120Electronic audit trails include those that track creation, modification, or deletionof data (such as processing parameters and results) and those that track actions at the record or system level (such as attempts to access the system or rename ordelete a file).CGMP-compliant record-keeping practices prevent data from being lost orobscured (see §§ 211.160(a), 211.194, and 212.110(b)). Electronic record-keeping systems, which include audit trails, can fulfill these CGMP requirements.d. How does FDA use the terms “static” and “dynamic” as they relate to recordformats?For the purposes of this guidance, static is used to indicate a fixed-data document such as a paper record or an electronic image, and dynamic means that the record format allows interaction between the user and the record content. For example, a dynamic chromatographic record may allow the user to change the baseline andreprocess chromatographic data so that the resulting peaks may appear smaller or121 122 123 124 125 126 127 128 129 130 131 132 133 134 135 136 137 138 139 140 141 142 143 144 145 146 147 148 149 150 151 152 153 154 155 156 157 158 159 160 161larger. It also may allow the user to modify formulas or entries in a spreadsheetused to compute test results or other information such as calculated yield.e. How does FDA use the term “backup” in § 211.68(b)?FDA uses the term backup in § 211.68(b) to refer to a true copy of the originaldata that is maintained securely throughout the records retention period (forexample, § 211.180). The backup file should contain the data (which includesassociated metadata) and should be in the original format or in a formatcompatible with the original format.This should not be confused with backup copies that may be created duringnormal computer use and temporarily maintained for disaster recovery (e.g., incase of a computer crash or other interruption). Such temporary backup copieswould not satisfy the requirement in § 211.68(b) to maintain a backup file of data.f. What are the “systems” in “computer or related systems” in § 211.68?The American National Standards Institute (ANSI) defines systems as people,machines, and methods organized to accomplish a set of specific functions.5Computer or related systems can refer to computer hardware, software, peripheraldevices, networks, cloud infrastructure, operators, and associated documents (e.g.,user manuals and standard operating procedures).2. When is it permissible to exclude CGMP data from decision making?Any data created as part of a CGMP record must be evaluated by the quality unit as part of release criteria (see §§ 211.22 and 212.70) and maintained for CGMP purposes (e.g., §211.180). Electronic data generated to fulfill CGMP requirements should include relevant metadata. To exclude data from the release criteria decision-making process, there must be a valid, documented, scientific justification for its exclusion (see the guidance forindustry Investigating Out-of-Specification (OOS) Test Results for PharmaceuticalProduction, and §§ 211.188, 211.192, and 212.71(b)). The requirements for recordretention and review do not differ depending on the data format; paper-based andelectronic data record-keeping systems are subject to the same requirements.3. Does each workflow on our computer system need to be validated?Yes, a workflow, such as creation of an electronic master production and control record (MPCR), is an intended use of a computer system to be checked through validation (see §§ 211.63, 211.68(b), and 211.110(a)). If you validate the computer system, but you do5American National Standard for Information Systems, Dictionary for Information Systems, American National Standards Institute, 1991.162 163 164 165 166 167 168 169 170 171 172 173 174 175 176 177 178 179 180 181 182 183 184 185 186 187 188 189 190 191 192 193 194 195 196not validate it for its intended use, you cannot know if your workflow runs correctly.6 Forexample, qualifying the Manufacturing Execution System (MES) platform, a computersystem, ensures that it meets specifications; however, it does not demonstrate that a given MPCR generated by the MES contains the correct calculations. In this example,validating the workflow ensures that the intended steps, specifications, and calculationsin the MPCR are accurate. This is similar to reviewing a paper MPCR and ensuring allsupporting procedures are in place before the MPCR is implemented in production (see§§ 211.100, 211.186, and 212.50(b), and the guidance for industry PET Drugs — Current Good Manufacturing Practice (CGMP)).FDA recommends you implement appropriate controls to manage risks associated witheach element of the system. Controls that are appropriately designed to validate a system for its intended use address software, hardware, personnel, and documentation.4. How should access to CGMP computer systems be restricted?You must exercise appropriate controls to assure that changes to computerized MPCRs, or other records, or input of laboratory data into computerized records, can be made only by authorized per sonnel (§ 211.68(b)). FDA recommends that you restrict the ability toalter specifications, process parameters, or manufacturing or testing methods by technical means where possible (for example, by limiting permissions to change settings or data).FDA suggests that the system administrator role, including any rights to alter files andsettings, be assigned to personnel independent from those responsible for the recordcontent. To assist in controlling access, FDA recommends maintaining a list ofauthorized individuals and their access privileges for each CGMP computer system inuse.If these independent security role assignments are not practical for small operations orfacilities with few employees, such as PET or medical gas facilities, FDA recommendsalternate control strategies be implemented.7 For example, in the rare instance that thesame person is required to hold the system administrator role and to be responsible forthe content of the records, FDA suggests having a second person review settings andcontent. If second-person review is not possible, the Agency recommends that the person recheck settings and his or her own work.6In computer science, validation refers to ensuring that software meets its specifications. However, this may not meet the definition of process validation as found in guidance for industry Process Validation: General Principlesand Practices: “The collection and evaluation of data … which establishes scientific evidence that a process is capable of consistently delivering quality products.” See also ICH guidance for industry Q7A Good Manufacturing Practice Guide for Active Pharmaceutical Ingredients, which defines validation as providing assurance that a specific process, method, or system will consistently produce a result meeting predetermined acceptance criteria. For purposes of this guidance, validation is being used in a manner consistent with the above guidance documents.7For further discussion of such alternate control strategies, see the guidance for industry PET Drugs — Current Good Manufacturing Practice (CGMP).197 198 199 200 201 202 203 204 205 206 207 208 209 210 211 212 213 214 215 216 217 218 219 220 221 222 223 224 225 226 227 228 229 230 231 232 233 234 235 236 237 238 239 240 241 242 5. Why is FDA concerned with the use of shared login accounts for computersystems?You must exercise appropriate controls to assure that only authorized personnel make changes to computerized MPCRs, or other records, or input laboratory data into computerized records, and you must implement documentation controls that ensure actions are attributable to a specific individual (see §§ 211.68(b), 211.188(b)(11),211.194(a)(7) and (8), and 212.50(c)(10)). When login credentials are shared, a unique individual cannot be identified through the login and the system would thus not conformto the CGMP requirements in parts 211 and 212. FDA requires that systems controls, including documentation controls, be designed to follow CGMP to assure product quality (for example, §§ 211.100 and 212.50).6. How should blank forms be controlled?There must be document controls in place to assure product quality (see §§ 211.100, 211.160(a), 211.186, 212.20(d), and 212.60(g)). FDA recommends that, if used, blank forms (including, but not limited to, worksheets, laboratory notebooks, and MPCRs) be controlled by the quality unit or by another document control method. For example, numbered sets of blank forms may be issued as appropriate and should be reconciled upon completion of all issued forms. Incomplete or erroneous forms should be kept as part of the permanent record along with written justification for their replacement (for example, see §§ 211.192, 211.194, 212.50(a), and 212.70(f)(1)(vi)).Similarly, bound paginated notebooks, stamped for official use by a document control group, allow detection of unofficial notebooks as well as of any gaps in notebook pages. 7. How often should audit trails be reviewed?FDA recommends that audit trails that capture changes to critical data be reviewed with each record and before final approval of the record. Audit trails subject to regular review should include, but are not limited to, the following: the change history of finishedproduct test results, changes to sample run sequences, changes to sample identification, and changes to critical process parameters.FDA recommends routine scheduled audit trail review based on the complexity of the system and its intended use.See audit trail definition 1.c. above for further information on audit trails.8. Who should review audit trails?Audit trails are considered part of the associated records. Personnel responsible for record review under CGMP should review the audit trails that capture changes to critical data associated with the record as they review the rest of the record (for example, §§211.22(a), 211.101(c), 211.194(a)(8), and 212.20(d)). For example, all production and243 244 245 246 247 248 249 250 251 252 253 254 255 256 257 258 259 260 261 262 263 264 265 266 267 268 269 270 271 272 273 274 275 276 277 278 279 280 281 282 283 284 285 control records, which includes audit trails, must be reviewed and approved by the quality unit (§ 211.192). This is similar to the expectation that cross-outs on paper be assessed when reviewing data.9. Can electronic copies be used as accurate reproductions of paper orelectronic records?Yes. Electronic copies can be used as true copies of paper or electronic records, provided the copies preserve the content and meaning of the original data, which includes associated metadata and the static or dynamic nature of the original records.True copies of dynamic electronic records may be made and maintained in the format of the original records or in a compatible format, provided that the content and meaning of the original records are preserved and that a suitable reader and copying equipment (for example, software and hardw are, including media readers) are readily available (§§211.180(d) and 212.110).10. Is it acceptable to retain paper printouts or static records instead of originalelectronic records from stand-alone computerized laboratory instruments,such as an FT-IR instrument?A paper printout or static record may satisfy retention requirements if it is a complete copy of the original record (see §§ 211.68(b), 211.188, 211.194, and 212.60). For example, pH meters and balances may create a paper printout or static image during data acquisition as the original record. In this case, the paper printout or static image created during acquisition, or a true copy, should be retained (§ 211.180).However, electronic records from certain types of laboratory instruments are dynamic records, and a printout or a static record does not preserve the dynamic format which is part of the complete original record. For example, the spectral file created by FT-IR (Fourier transform infrared spectroscopy) can be reprocessed, but a static record or printout is fixed, which would not satisfy CGMP requirements to retain original recordsor true copies (§ 211.180(d)). Also, if the full spectrum is not displayed, contaminantsmay be excluded.Control strategies must ensure that original laboratory records, including paper and electronic records, are subject to second-person review (§ 211.194(a)(8)) to make certain that all test results are appropriately reported.For PET drugs, see the guidance for industry PET Drugs — Current Good Manufacturing Practice (CGMP) for discussion of equipment and laboratory controls, including regulatory requirements for records.286 287 288 289 290 291 292 293 294 295 296 297 298 299 300 301 302 303 304 305 306 307 308 309 310 311 312 313 314 315 316 317 318 319 320 321 322 323 324 325 326 327 328 329 330 331 11. Can electronic signatures be used instead of handwritten signatures formaster production and control records?Yes, electronic signatures with the appropriate controls can be used instead of handwritten signatures or initials in any CGMP required record. While § 211.186(a) specifies a “full signature, handwritten,” as explained in the Federal Register on September 29, 1978 (43 FR 45069), part of the intent of the full signature requirement is to be able to clearly identify the individual responsible for signing the record. An electronic signature with the appropriate controls to securely link the signature with the associated record fulfills this requirement. This comports with part 11, which establishes criteria for when electronic signatures are considered the legally binding equivalent of handwritten signatures. Firms using electronic signatures should document the controls used to ensure that they are able to identify the specific person who signed the records electronically.There is no requirement for a handwritten signature for the MPCR in the PET CGMP regulations (21 CFR part 212).12. When does electronic data become a CGMP record?When generated to satisfy a CGMP requirement, all data become a CGMP record. You must document, or save, the data at the time of performance to create a record in compliance with CGMP requirements, including, but not limited to, §§ 211.100(b) and 211.160(a). FDA expects processes to be designed so that quality data required to be created and maintained cannot be modified. For example, chromatograms should be sent to long-term storage (archiving or a permanent record) upon run completion instead of at t he end of a day’s runs.It is not acceptable to record data on pieces of paper that will be discarded after the data are transcribed to a permanent laboratory notebook (see §§ 211.100(b), 211.160(a), and 211.180(d)). Similarly, it is not acceptable to store data electronically in temporary memory, in a manner that allows for manipulation, before creating a permanent record. Electronic data that are automatically saved into temporary memory do not meet CGMP documentation or retention requirements.You may employ a combination of technical and procedural controls to meet CGMP documentation practices for electronic systems. For example, a computer system, such as a Laboratory Information Management System (LIMS) or an Electronic Batch Record (EBR) system, can be designed to automatically save after each separate entry. This would be similar to recording each entry contemporaneously on a paper batch record to satisfy CGMP requirements. The computer system could be combined with a procedure requiring data be entered immediately when generated.For PET drugs, see the “Laboratory Controls” section of the guidance for industry PET Drugs — Current Good Manufacturing Practice (CGMP).。

FDA重磅发布数据完整性指南草案近几年，由于数据完整性问题，FDA在例行检查或是飞行检查后，由于数据完整性问题，给他们的药品生产商发出了左一封警告信，左一封不合格报告，包括浙江九洲药业、浙江海正药业、大连辉瑞制药等频频中招。

到底什么是数据完整性？在业界翘首企盼中，美国FDA CDER于2016年4月14日发布了数据完整性（Data Integrity）行业指南草案。

数据完整性指南草案是以问题解答的方式发布的，共１８个问题。

该指南解析了什么是数据完整性、元数据、系统、审计跟踪、备份、动态和静态记录。

其中就本指南而言，数据完整性是指完全、一致和准确性。

完全、一致和准确的数据应该是有归属性、清晰易读性、即时性、原始记录或是真实副本和准确性无误性(ALCOA)。

审计追踪是一种安全得、由计算机系统生成的、有时间标识的电子记录，它能够创建电子记录产生、修改或者删除的整个事件过程。

审计追踪是一份关于“谁、什么、何时为什么”的记录的时序表。

FDA指南草案中关于“系统”的定义，很值得关注。

指南引用了美国国家标准学会（ANSI）的定义将系统定义为组织人、机器和方法以完成一系列的具体功能。

计算机或相关系统指计算机、硬件、软件、外围设备、网络、云基础设施、操作人员（operators）和相关文件（例如，用户手册和标准操作规程）。

这也是指南中没有引用CGMP条款的地方之一。

该指南草案还提出了如何限制对计算机系统的访问权限、FDA为什么担心公用账户问题、怎样控制空白记录、审计追踪的频次及谁来审计追踪、电子拷贝问题、电子数据问题、系统适应性问题、公司内部的有关潜在的数据造假的举报应该如何处理、识别数据完整性问题应该作为人员CGMP常规培训计划的一部分、公司如何处理FDA或其他药监机构发现了数据完整性问题等。

随着草案的实施，如今数据完整性已经上升为一种指南，监管药品生产企业，需要我们制药企业认真学习该草案，并深入贯彻实施。

对美国CGMP顾问harbata 先生CGM审计结束的那两句话至今记忆犹新：- A place for everything and everything in its place。

FDA检查涉及的部分数据完整性案例简析FDA检查的企业数据完整性缺陷主要有以下几种情形：1）部分记录数据真实性存疑；2）电子数据的安全性不足，例如未采取措施防止未授权人员访问、修改数据，无法保证数据不被删除，没有开启审计追踪功能等；3）未记录或及时记录全部的数据和信息；4）缺乏对文件和记录的有效控制等。

以下是对该14家企业存在的有关数据完整性缺陷的翻译，仅供参考。

1、企业名称：Cadila Pharmaceuticals Limited1）企业没有采取措施防止未授权人员访问或修改数据，并能防止数据的缺失。

企业没有合适的控制措施防止未授权人员处理原始电子数据。

例如a. 现场检查发现自2013年10月起企业气相色谱仪（GC）的审计追踪功能就不曾使用过，然而2009 GC 软件验证包括了对审计追踪功能的评估，显示该功能令人满意。

b.企业无法确保GC、Malvern粒度分析仪和紫外分光光度计原始检测数据的完整性。

检查员发现这些仪器只与一台电脑相连存储数据，这些数据可以被删除。

c.此次检查之前，你公司对**傅里叶变换红外光谱仪、偏光计、紫外分光光度计以及Malvern粒度分析仪的数据备份失败。

检查还发现一些稳定性考察的样品未在规定的时间间隔内进行检测。

企业2014年稳定性考察方案仍积压在案，因而延误了样品检测，但质量管理部门并未引起重视。

类似的情况在2012年的现场检查中也出现过。

2、企业名称：Novacyl Wuxi Pharmaceutical Co., Ltd.1）对QC实验室管理控制不充分，无法确保检验结果符合质量标准，并能防止数据的缺失。

现场检查发现企业文件管理方面存在包括原始数据缺失在内的严重缺陷。

确保企业保留有原始支持性数据，证明原料药符合既定预期的质量标准，是质量部门的基本职责。

例如，检查员在垃圾堆中发现与某产品相关的原料药色谱图（日期为2013年10月15日）。

与标准图谱进行比对发现该色谱图多了一个色谱峰。

美国FDA于2016年4月14日发布了数据完整性（Data Integrity）的行业指南。

1．FDA的这个指南仅适用于CGMP, 而不是GxP。

MHRA的指南也是只适用于GMP，但是MHRA正在考虑修改其指南，将其扩展到GxP。

WHO的良好数据管理指南则是适用于GxP。

2．不同于以往其它的FDA的指南，DI的指南是以问题解答的方式发布的。

共１８个问题。

问题1是名词解析。

包括DI，元数据，系统，审计跟踪，备份，动态和静态记录。

其中对DI的定义是完全、一致和准确的数据，进一步明确了完全、一致和准确的数据应具备ALCOA要求。

3．也许是因为该指南仅适用于CGMP，该指南里的18个问题，除了两个没有提到具体的GMP相关的条款外，其它的都引用了相应的GMP条款，主要包括CFR210、CFR211、CFR212和Part11的要求。

其中特别提到的是CFR211.68、100、160、180、188、211、194和CFR212.110、60。

4．FDA指南中关于“系统”的定义，很值得关注。

指南引用了美国国家标准学会（ANSI）的定义将系统定义为组织人、机器和方法以完成一系列的具体功能。

计算机或相关系统指计算机、硬件、软件、外围设备、网络、云基础设施、操作人员（operators）和相关文件（例如，用户手册和标准操作规程）。

这也是指南中没有引用CGMP条款的地方之一。

值得注意的是FDA的指南将系统的范围扩大了，引入了外围设备、云，尤其是引入了操作人员和操作规程。

5．何时允许将CGMP数据从决策制定中排除？简单的说就是所有的CGMP数据都必须在产品放行时被考虑并保存；不考虑某些数据必须要有理有据，有记录，有科学依据。

这个要求对纸质记录和电子记录是一样的。

6．我们计算机系统上的每个工作流均需要被验证？问题3要求计算机系统验证要对每一个工作流程（workflow）进行验证，而不是仅仅考虑系统是否符合技术要求。

比如要验证MES（manufacturing execution system）系统，其验证要证明工艺过程中的步骤、标准、计算都准确无误。

FDA制剂厂检查指南对制剂企业的检查-CGMP备注：这个文件是对检查者和其他的FDA官员的参照。

这份文件并不限制FDA，并不获取任何利益，义务，权利，或豁免某人1简介这个文件介绍到一个大约的药厂检查指导他们是否符合药物的CGMP。

这个指导应该被用来作IOM的介绍，其他的药物检查指导，和复核项目。

这个检查的指导相对于IOM的第十章，一些指导是：A 原料药视察指导B 高纯水系统视察的指导C QC实验室视察的指导D 微生物QC实验室的指导E 冻干注射剂视察的指导F 清洁验证视察的指导G 制药过程中的计算机系统的视察的指导H 一般工艺过程验证的指导2 CGMP处方和非处方所有的药物的生产过程要对应于CGMP否则就被认为在FDC实施中掺假。

501(a)(2)(B)依据处方药物的记录一定要对照于704(a)(1)(B)章。

如果药物是OTC药物被NDA或ANDA覆盖，FDA可以回顾，复制，验证在505(k)(2)章下的FDC。

然而，如果产品是在FDA没注册过的OTC药物。

并没有法定的严格要求在视察过程中给视察者看的的记录要按704章FDC的要求。

而且，所有的处方药和OTC 药的生产必须符合CGMP的要求，包括那些记录。

视察者应该回顾这些记录作为决定是否符合CGMP要求的一部分。

在很少的场合，可以拒绝回顾OTC的记录因为并没有法定要求这样做。

当工厂在没有法定义务去提供回顾这些记录时，没有减轻需要符合在501(a)(2)(B)CGMP 的要求，包括对主体文件的要求。

如果一个工厂拒绝回顾OTC的记录，视察者应该被其他的视察方法决定特别符合CGMP的要求。

视察者观察和查找对于处方药和非处方药并不根据FDA-483确定的检查表中做的行为。

组织和人员工厂一定要有QC控制文件描述CFR的责任和权威。

QC文件一定要在表明它的相对于生产文件的独立性，在书面表明它的责任权属。

表明操作者的官员的名字，头衔和内在的责任，其他的主要的职员在IOM中列出。